A number of compounds have been described which are competitive reversible inhibitors of zinc-containing metalloproteinase enzymes. Such competitive reversible inhibitors include for example inhibitors of the angiotensin converting enzymes (ACE). Such an inhibitor acts to block conversion of the decapeptide angiotensin I to angiotensin II, a potent pressor substance. ACE inhibitors are of use in the treatment of hypertension. Compounds of this type are for example described in European Patent Application No. A-0012401. Related inhibitors of the enzyme enkephalinase are described in EPA No. 0054862.
The compounds of the present invention act as inhibitors of mammalian collagenase [EC 3.4.24.7] which initiates collagen breakdown. There is evidence (for example Arthritis and Rheumatism, 20, 1231-1239, 1977) implicating the involvement of the zinc metalloproteinase, collagenase, as one of the key enzymes in the degradation of articular cartilage and bone in rheumatoid arthritis. Collagen is one of the major components of the protein matrix of cartilage and bone. Potent inhibitors of collagenase are useful in the treatment of rheumatoid arthritis and associated diseases in which collagenolytic activity is a contributing factor. These diseases include corneal ulceration, osteoporosis, periodontitis, gingivitis, tumour invasion and dystrophic epidermolysis bullosa.
U.S. Pat. No. 4,511,504 describes a class of novel carboxyalkyl peptide derivatives which are useful as collagenase inhibitors. U.S. application Ser. No. 06/703,973, filed Feb. 2, 1985, describes a class of thiol based collagenase inhibitors which are useful in the treatment of diseases in which collagenase promoted collagen breakdown is a causative factor.